Pharmacologic treatment options for many substance use disorders (SUDs) are limited. This is especially true for cocaine use disorder and cannabis use disorder, for which there are no FDA-approved medications. FDA-approved medications for other SUDs often take the form of replacement or agonist therapies (eg, nicotine replacement therapy) that substitute the effects of the substance to aid in cessation. Other pharmacotherapies treat symptoms of withdrawal, reduce craving, or provide aversive counter-conditioning if the patient consumes the substance while on the medication (eg, disulfiram).

The over-the-counter (OTC) antioxidant N-acetylcysteine (NAC) may be a potential treatment for SUDs. Although NAC is not approved by the FDA for treating SUDs, its proposed mechanism of action differs from that of current FDA-approved medications for SUDs. NAC's potential for broad applicability, favorable adverse-effect profile, accessibility, and low cost make it an intriguing option for patients with multiple comorbidities, and potentially for individuals with polysubstance use. This article reviews the current evidence supporting NAC for treating SUDs, to provide insight about which patients may benefit from NAC and under which circumstances they are most likely to benefit.

NAC may correct glutamate dysregulation

Approximately 85% of individuals with an SUD do not seek treatment for it, and those who do are older, have a longer history of use, have more severe dependence, and have sought treatment numerous times before. (1) By the time most people seek treatment, years of chronic substance use have likely led to significant brain-related adaptations. Individuals with SUDs often indicate that their substance use began as a pleasurable activity--the effects of the drug were enjoyable and they were motivated to use it again. With repeated substance use, they may begin to develop a stronger urge to use the drug, driven not necessarily by a desire for pleasure, but by compulsion. (2)

Numerous neural adaptations underlie the transition from "liking" a substance to engaging in the compulsive use that is characteristic of an SUD. (2) For example, repeated use of an addictive substance may result in excess glutamate in the nucleus accumbens, (3,4) an area of the brain that plays a critical role in motivation and learning. As a result, it has been proposed that pharmacotherapies that help correct glutamate dysregulation may be effective in promoting abstinence or preventing relapse to a substance. (5,6)

NAC may reverse the neural dysfunction seen in SUDs. As an OTC antioxidant that impacts glutamatergic functioning in the brain, NAC has long been used to treat acetaminophen overdose; however, in recent years, researchers have begun to tap its potential for treating substance use and psychiatric disorders. NAC is thought to upregulate the glutamate transporter (GLT-1) that removes excess glutamate from the nucleus accumbens. (6) Several published reviews provide more in-depth information about the neurobiology of NAC. (6-10)

The adverse-effect profile of NAC is relatively benign. Nausea, vomiting, diarrhea, and sleepiness are relatively infrequent and mild. (11,12) The bioavailability of NAC is about 4% to 9%, with an approximate half-life of 6.25 hours when orally administered. (13) Because NAC is...